Johns
Hopkins Kimmel Cancer Center scientists have found that
interferon, used for 30 years to treat blood cancers,
multiple sclerosis and hepatitis, selectively kills colon
cancer cells when combined with another standard
chemotherapy agent. New studies in cell lines suggest that
the combination tactic, which targets a common gene pathway
in colon cancer cells, could be more potent than either
drug alone and has fewer side effects.

"Instead of killing a tree by chopping it down, this
approach focuses on cutting off the diseased branch,
leaving the rest of the tree relatively unscathed," Betsy
Barnes, assistant professor of oncology in the School of
Medicine and lead researcher, said.

By itself, interferon's cell-killing activity is
nonspecific in targeting a variety of cells and cell-based
gene activity, causing serious side effects such as heart
failure and low blood counts in addition to killing cancer
cells. But in an Aug. 15 issue of Cancer Research, the
Kimmel Cancer Center scientists found one factor in
interferon's makeup that could have cancer-killing
qualities but with fewer side effects since it activates
fewer genes.

Specifically, the team found that IRF5 (Interferon
Regulatory Factor-5), which works as a tumor suppressor to
halt cancer cell growth, is turned off by many cancers, but
low levels of the suppressor protein are found in most
colon cancers. That led Barnes and her team to pursue its
potential.

The first thing they found is that although interferon
boosts IRF5 protein levels in colon cancer cells, it does
not raise them enough to kill the cells. To boost IRF5
levels, the investigators combined interferon with a
chemotherapy drug called irinotecan, or CPT-11, a drug that
damages DNA in rapidly dividing cells, rendering them
unable to divide.

"We believe that interferon and irinotecan both work
to increase IRF5 protein levels, but irinotecan activates
the protein in the final step to initiate cancer cell
death," Barnes said.

To demonstrate their theory that IRF5 is a key
ingredient in the dual-drug therapy, the scientists tested
various combinations of the drugs in colon cancer cell
lines, with or without IRF5. Irinotecan alone causes 65
percent cell death in lines with IRF5 proteins present.
Knock out IRF5 proteins, and cell deaths drop to 37
percent. When the investigators combined irinotecan and
interferon, more than 80 percent of colon cancer cells with
IRF5 proteins died. Only 28 percent of cells died in those
lines with IRF5 proteins knocked out.

"Not only does the combination of these drugs involve
fewer gene activations, it may allow use of smaller amounts
of both drugs and limit side effects," Barnes said. Also,
cancer cells may find it more difficult to build resistance
to two different drugs, a common problem when using single
agents, she said.

Cancers lacking tumor suppressor genes and the
proteins they make are often difficult to treat because
cells are unable to put the brake on abnormal growth.
Barnes' study indicates that IRF5 applies the brakes even
in the absence of other tumor suppressor genes.

It is not clear whether the combination therapy would
work in other cancers, since IRF5 is absent in a number of
blood cancers. But since colon cancer is the third
deadliest cancer in the United States, Barnes and her team
will conduct further tests in genetically modified mice and
potentially create a new strategy to treat the disease.

Colon cancer strikes more than 100,000 people in the
United States annually and kills more than 56,000.

Funding for this research was provided by the American
Cancer Society and a Flight Attendant Medical Research
Institute Young Clinical Scientist Award.

Barnes' research team on this study included Guodong
Hu and Margo E. Mancl, both of Johns Hopkins.